Isolation, characterization and pathogenic role of self-propagating conformational amyloid-beta strains

University Of Texas Hlth Sci Ctr Houston, Houston TX

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Abstract

ABSTRACT A hallmark event in Alzheimer's disease (AD) is the misfolding, aggregation and brain accumulation of the amyloid-? peptide (A?). Recent reports have shown that A? aggregates can spread the pathological abnormalities following a similar principle by which prions transmit prion disease in an infectious manner. Both prions, A? and other misfolded proteins are formed by a seeding-nucleation mechanism, which has the intrinsic ability to be transmissible. Over the past 5 years, many of the hallmark properties of prions has been shown to be shared by A? aggregates. In particular, several lines of evidence have shown that A? can adopt different prion-like conformational strains, which may explain the large neuropathological and clinical heterogeneity observed among different AD patients. The major goal of this project is to comprehensibly study the phenomenon of A? conformational strains using various biochemical, biological and structural techniques and develop new tools to discriminate between strains and identify their presence in patients' samples. Our working hypothesis is that upon misfolding and aggregation, A? can adopt multiple stable conformational strains with distinct biochemical, biological and structural features, which are responsible for the heterogeneity in neuropathological and clinical manifestations observed in AD patients. We also propose that different conformational strains can be detected in biological fluids of patients by an in vitro seeding/amplification assay, which will serve to stratify patients, predict disease onset and progression and for personalized treatment. To achieve this goal, we propose to study the following specific aims: (1) Study the biochemical, biophysical and biological properties of structurally-defined synthetic A? strains; (2) Isolation, propagation and characterization of new natural A? strains from AD brains; (3) Detection of A? strains in biological fluids of AD patients and its use for disease diagnosis. The findings generated in this project may contribute to better understand the extent to which the prion principle operates in A? aggregates, particularly in relation to the intriguing feature of prion strain variability. Our results may support the concept that misfolded A? aggregates naturally exist as diverse stable conformational variants associated with different pathogenicity and responsible for distinct clinical phenotypes. These findings will have not only a great impact in understanding the molecular basis of AD, but may contribute substantially to the development of effective treatments for this disease. Indeed, our data may uncover the biochemical and structural features of the A? aggregates most relevant for disease spreading and pathogenicity, which will represent the best targets for therapeutic intervention. Our results may also serve to guide clinical development of therapeutic candidates by defining which conformational strains a certain treatment may target. If successful, our findings on the detection and identification of conformational strains in biological fluids will have not only a clear impact for disease diagnosis, but may also pave the way for future efforts of a personalized treatment for AD patients.